CDC2-RELATED PROTEINS AND THE CONTROL OF CELL DIVISION

此申请是为临床研究人员奖，以提供支持 在从博士后培训到职业生涯的过渡时期 一名独立调查员。申请人接受了博士前培训。 在NIH赞助的医学科学家培训计划中，紧随其后的是 接受内科和消化内科临床培训，并拥有 回到实验室研究分子机制 控制人类细胞分裂。 最近在两个相关但很大程度上取得进展 独立的研究领域，真核细胞周期的控制 以及恶变的机制。两者的分离 菲尔兹的部分原因是缺乏对分子的了解。 在高等真核生物中控制细胞分裂的事件。因此，它 仍不清楚已被识别的各种癌基因是如何 最终扰乱细胞增殖的正常控制。 在细胞周期方面的大部分进展来自于在较低的 真核生物。在酵母中，一种指定为细胞分裂控制的蛋白激酶 蛋白2(Cdc2)调节细胞周期的两个主要转变，进入 进入DNA合成和有丝分裂。现在很明显，这一点 蛋白质调节包括人类在内的所有真核生物有丝分裂的开始。 然而，目前还没有证据表明cdc2在早期细胞中起作用。 高等真核生物中的循环事件。 最近，一种密切相关的蛋白激酶在几个 高等真核生物，对DNA合成是必不可少的，并与 人腺病毒的主要转化蛋白。这些观察结果 确定至少两个密切相关的蛋白激酶控制细胞 高等真核生物中的分裂，这些酶可能是 恶变。我们最近又鉴定出五种蛋白质 人类细胞中与cdc2密切相关的激酶。这项建议是 为了研究这些蛋白质的子集的正常功能，通过分析 细胞周期中处于活跃状态的时间点及其对细胞周期的影响 消融它们活动的细胞。这项工作将进一步定义正常 对人类细胞分裂的控制和潜在的转化目标 蛋白质。

This application is for a Clinical Investigator Award, to provide support during a period of transition from post-doctoral training to a career as an independent investigator. The applicant received predoctoral training in the NIH-sponsored Medical Scientist Training Program, followed by clinical training in Internal Medicine and Gastroenterology, and has returned to the laboratory to investigate the molecular mechanisms that control human cell division. Substantial progress has recently been made in two related but largely separate areas of investigation, the control of the eucaryotic cell cycle and the mechanisms of malignant transformation. The separation of the two fields has in part been due to a lack of understanding of the molecular events that control cell division in higher eucaryotes. As a result, it has remained unclear how the various oncogenes that have been identified ultimately disrupt the normal controls on cell proliferation. Much of the progress on the cell cycle has come from work in lower eucaryotes. In yeasts a protein kinase designated cell division control protein 2 (cdc2) regulates both major transitions in the cell cycle, entry into DNA synthesis and entry into mitosis. It is now evident that this protein regulates the onset of mitosis in all eucaryotes, including man. However, there has been no evidence for a role for cdc2 in earlier cell cycle events in higher eucaryotes. Recently a closely related protein kinase has been identified in several higher eucaryotes that is essential for DNA synthesis and associates with the principle transforming protein of human adenovirus. These observations establish that at least two closely related protein kinases control cell division in higher eucaryotes and that these enzymes may be targets of malignant transformation. We have recently identified five more protein kinases in human cells that are closely related to cdc2. This proposal is to study the normal function of a subset of these proteins, by analyzing the points in the cell cycle when they are active and the effects on the cell of ablating their activity. This work will further define the normal controls over human cell division and potential targets for transforming proteins.